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Background/objectives: Survivin is an oncogene associated with a decrease in apoptosis, an increase in tumor growth, and poor clinical outcome of diverse malignancies. A correlation between obesity, cancer, and survivin is reported in the literature. To date, the impact of weight loss on change in survivin levels is understudied. This study was aimed at: (1) comparing survivin levels in adipose tissue (AT) from lean and obese animal models and evaluating changes after weight loss induced by energy restriction and/or exercise; (2) comparing survivin levels in normal weighted and obese humans and evaluating changes in survivin levels after weight loss induced by a very-low-calorie ketogenic diet (VLCKD) or bariatric surgery in AT and/or blood leukocytes (PBL/PBMCs). Subjects/methods: Survivin expression was evaluated in subcutaneous (SAT) and visceral (VAT) AT derived from animal models of monogenic (Zucker rats) and diet-induced obesity (Sprague Dawley rats and C57BL/6J mice) and after a 4-week weight-loss protocol of energy restriction and/or exercise. Plasma was used to measure the inflammatory status. Survivin expression was also evaluated in PBMCs from patients with obesity and compared with normal weight, in PBLs after VLCKD, and in SAT and/or PBLs after bariatric surgery. Results: Survivin expression was specifically higher in VAT from obese that lean animals, without differences in SAT. It decreased after weight loss induced by energy restriction and correlated with adiposity and inflammatory markers. In humans, the correlation between being obese and higher levels of survivin was confirmed. In obese subjects, survivin levels were reduced following weight loss after either VLCKD or bariatric surgery. Particularly, a decrease in PBMCs expression (not in SAT one) was found after surgery. Conclusions: Weight loss is effective in decreasing survivin levels. Also, PBL/PBMC should be regarded as appropriate mirror of survivin levels in VAT for the identification of an obesity-related protumoral microenvironment.

No relevant conflicts of interest to declare.

Iron overload causes the generation of reactive oxygen species, which can lead to liver failure, particularly when it occurs in conjunction with nonalcoholic fatty liver disease (NAFLD) or viral hepatitis. Previously, we studied the effects of iron deficiency and iron overload on the hepatic transcriptional and metabolomic profile in mice. We found that iron overload induced significant changes in the expression of genes and metabolites involved in glucose and nicotinamide metabolism in both a dietary model, high iron diet, and a genetic model, hemojuvelinknockout mice. In particular, we discovered that the transcript, Nicotinamide N-methyltransferase(NNMT), was significantly downregulated in both models of iron overload. NNMT methylates nicotinamide, a form of vitamin B3, and has recently been shown to play a critical role in hepatic glucose and cholesterol metabolism by stabilizing Sirtuin 1, a nicotinamide-dependent deacetylase. For the current study, we evaluated 63 morbidly obese human subjects who gave written informed consent, validated and approved by the ethical committee of the Hospital Universitari Dr. Josep Trueta (Comitè d’Ètica d’Investigació Clínica, approval number 2009046), for the collection of liver biopsy samples and sera at the time of bariatric surgery after 8 hours of fasting. In these subjects, we found that log hepatic transcript levels of NNMTnegatively correlated with measures of body iron stores, including log serum ferritin levels (R=-0.39, p=0.002) and log percent transferrin saturation (R=-0.21, p=0.02). We then performed experiments in primary hepatocytes to evaluate the interaction of iron overload and NNMT. We found that treatment with ferric ammonium citrate significantly decreased NNMTtranscript levels in either primary human or mouse hepatocytes. We manipulated NNMTexpression in primary mouse hepatocytes using adenoviral vectors and discovered that NNMTknockdown exacerbated iron-induced cytotoxicity and enhanced iron-induced expression of transcriptional markers of oxidative and endoplasmic reticulum stress, while NNMToverexpression protected against iron-induced cytotoxicity. In future studies, we would like to elucidate the mechanisms by which NNMT modulates hepatocyte sensitivity to iron overload. A deeper understanding of the relationship of the pathways involved in maintaining iron and energy homeostasis may reveal new therapeutic targets for patients with iron overload disorders, obesity, and NAFLD.